Oocyte stage-specific effects of MTOR determine granulosa cell fate and oocyte quality in mice

Area of Science:

• Reproductive biology
• Cellular signaling
• Developmental biology

Background:

• Mechanistic target of rapamycin (MTOR) integrates signals critical for cellular metabolism, proliferation, and differentiation.
• MTOR signaling is essential for female reproductive processes, including oocyte development and function.

Purpose of the Study:

• To investigate the role of MTOR in oocyte development and function by examining the consequences of its conditional knockout (cKO) in primordial and growing oocytes.
• To elucidate the differential effects of MTOR deletion at distinct oocyte developmental stages on oocyte quality, granulosa cell fate, and follicular development.

Main Methods:

• Conditional knockout (cKO) of the Mtor gene in mouse oocytes at specific developmental stages (primordial and growing).
• Analysis of follicular development, oocyte quality, granulosa cell identity, DNA damage accumulation, and transcriptomic alterations.
• Assessment of meiotic progression and preimplantation developmental competence.

Main Results:

• cKO of Mtor in primordial oocytes resulted in defective folliculogenesis, oocyte degeneration, and granulosa cell transformation into Sertoli cell-like cells.
• DNA damage accumulated in oocytes post-Mtor deletion, with significant transcriptomic changes observed in the few oocytes reaching full growth.
• cKO of Mtor in growing oocytes compromised oocyte quality and fertility without overtly affecting folliculogenesis, but impaired meiotic division completion due to PRC1 downregulation.

Conclusions:

• MTOR signaling in oocytes plays distinct roles depending on the developmental stage.
• MTOR is crucial for maintaining granulosa cell identity, oocyte genome integrity, and proper meiotic progression.
• Disruption of MTOR pathways in oocytes leads to infertility and affects preimplantation developmental competence.